Publication date: Nov 24, 2019
Reduced levels of neural activity are associated with a longer lifespan in the nematode C. elegans and in mice. Augmented neural activity is associated with a shorter lifespan. Recent studies show that levels of repressor element 1-silencing transcription factor (REST), increases with normal aging in mice and humans, and reduces neuronal excitation. In C. elegans, increased expression of spr-4, a functional REST homologue, increased the worm lifespan and is required for classical lifespan increase mediated by reduced DAF2/insulin-IGF-1 and increased DAF16. Preliminary evidence shows that REST and FOXO1, a DAF16, homolog increase during mammalian aging, and that REST activity is needed for the age-related FOXO1 increase. On the other hand, REST is activated in epilepsy and plays a role in the pathogenesis of Huntington’s disease. A simple unifying hypothesis suggests that REST is a “goldilocks-effect factor”: too little REST promotes excitotoxic activity, which in turn leads to neurodegenerative diseases like Alzheimer’s. Appropriate increased levels of REST maintain excitation-inhibition (E-I) balance by reducing potential excitotoxic activity. Increased levels of REST beyond this is toxic as neurons become dysfunctional due to loss of a neuronal phenotype.
Larrick, J. and Mendelsohn, A.R. Increased REST to optimize lifespan? 06795. 2019 Rejuvenation Res.
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